2024
Intestinal tuft cell immune privilege enables norovirus persistence
Strine M, Fagerberg E, Darcy P, Barrón G, Filler R, Alfajaro M, D'Angelo-Gavrish N, Wang F, Graziano V, Menasché B, Damo M, Wang Y, Howitt M, Lee S, Joshi N, Mucida D, Wilen C. Intestinal tuft cell immune privilege enables norovirus persistence. Science Immunology 2024, 9: eadi7038. PMID: 38517952, PMCID: PMC11555782, DOI: 10.1126/sciimmunol.adi7038.Peer-Reviewed Original ResearchConceptsCD8<sup>+</sup> T cellsIntestinal tuft cellsT cellsTufted cellsViral persistenceSite of viral persistenceChemosensory epithelial cellsNormal antigen presentationImmune-privileged nicheIntestinal stem cellsMemory phenotypeImmune privilegeImmune escapeReporter miceAntigen presentationChronic infectionCytotoxic capacityEpithelial cellsNorovirus infectionStem cellsCell interactionsInfectionCell survivalEnteric microbesCells
2023
IFN-λ derived from nonsusceptible enterocytes acts on tuft cells to limit persistent norovirus
Ingle H, Makimaa H, Aggarwal S, Deng H, Foster L, Li Y, Kennedy E, Peterson S, Wilen C, Lee S, Suthar M, Baldridge M. IFN-λ derived from nonsusceptible enterocytes acts on tuft cells to limit persistent norovirus. Science Advances 2023, 9: eadi2562. PMID: 37703370, PMCID: PMC10499323, DOI: 10.1126/sciadv.adi2562.Peer-Reviewed Original ResearchConceptsIntestinal epithelial cellsTuft cellsUninfected bystander cellsIFN-λ signalingSource of IFNImmune cellsIntestinal infectionsLeading causeViral gastroenteritisMNoVNorovirus pathogenesisCellular tropismPotent antiviralEpidemic viral gastroenteritisEpithelial cellsBystander cellsIFNNorovirusAntiviralsInfectionMurine norovirusIntercellular communicationPersistent strainsCellsVivoMurine Norovirus: Additional Protocols for Basic and Antiviral Studies
Wobus C, Peiper A, McSweeney A, Young V, Chaika M, Lane M, Lingemann M, Deerain J, Strine M, Alfajaro M, Helm E, Karst S, Mackenzie J, Taube S, Ward V, Wilen C. Murine Norovirus: Additional Protocols for Basic and Antiviral Studies. Current Protocols 2023, 3: e828. PMID: 37478303, PMCID: PMC10375541, DOI: 10.1002/cpz1.828.Peer-Reviewed Original ResearchAge-associated features of norovirus infection analysed in mice
Kennedy E, Aggarwal S, Dhar A, Karst S, Wilen C, Baldridge M. Age-associated features of norovirus infection analysed in mice. Nature Microbiology 2023, 8: 1095-1107. PMID: 37188813, PMCID: PMC10484054, DOI: 10.1038/s41564-023-01383-1.Peer-Reviewed Original ResearchConceptsViral uptakeWild-type neonatal miceCortisone acetate administrationAdaptive immune responsesInterferon-stimulated gene expressionIntestinal tuft cellsSeverity of infectionAbsence of interferonAge-associated variabilityAge-associated featuresMNoV infectionAcetate administrationViral exposureAntibody responseEnteric infectionsNeonatal miceInfected damsNorovirus infectionHigh burdenImmune responsePersistent infectionViral RNA accumulationIleal absorptionJuvenile miceAdult mice
2022
Tuft-cell-intrinsic and -extrinsic mediators of norovirus tropism regulate viral immunity
Strine M, Alfajaro M, Graziano V, Song J, Hsieh L, Hill R, Guo J, VanDussen K, Orchard R, Baldridge M, Lee S, Wilen C. Tuft-cell-intrinsic and -extrinsic mediators of norovirus tropism regulate viral immunity. Cell Reports 2022, 41: 111593. PMID: 36351394, PMCID: PMC9662704, DOI: 10.1016/j.celrep.2022.111593.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCaliciviridae InfectionsHumansMiceMice, Inbred C57BLNorovirusTropismViral TropismTuft cells are key mediators of interkingdom interactions at mucosal barrier surfaces
Strine MS, Wilen CB. Tuft cells are key mediators of interkingdom interactions at mucosal barrier surfaces. PLOS Pathogens 2022, 18: e1010318. PMID: 35271673, PMCID: PMC8912186, DOI: 10.1371/journal.ppat.1010318.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsInterkingdom interactionsTuft cellsCell biologyImmune responseMicrobial activationMicrobial sensingCell abundanceMucosal barrier surfacesAntiviral adaptive immune responsesType 2 immune responsesCell heterogeneityExquisite specificityMucosal barrier integrityAdaptive immune responsesMurine norovirusHuman healthKey orchestratorsMicrobial infectionsPathogenic bacteriaBroad intraFlavivirus replicationKey mediatorContext of coinfectionTissue repairImmune evasionRestriction of Viral Replication, Rather than T Cell Immunopathology, Drives Lethality in Murine Norovirus CR6-Infected STAT1-Deficient Mice
Sharon AJ, Filyk HA, Fonseca NM, Simister RL, Filler RB, Yuen W, Hardman BK, Robinson HG, Seo JH, Rocha-Pereira J, Welch I, Neyts J, Wilen CB, Crowe SA, Osborne LC. Restriction of Viral Replication, Rather than T Cell Immunopathology, Drives Lethality in Murine Norovirus CR6-Infected STAT1-Deficient Mice. Journal Of Virology 2022, 96: e02065-21. PMID: 35107369, PMCID: PMC8941907, DOI: 10.1128/jvi.02065-21.Peer-Reviewed Original ResearchConceptsAntiviral T cell responsesT cell responsesSTAT1-deficient miceSystemic viral infectionCell responsesViral replicationViral infectionTissue damageViral-induced tissue damageVirus-induced tissue damageAltered T-cell responsesLimited viral replicationT cell immunopathologyOngoing inflammatory responseAdaptive immune cellsUncontrolled viral replicationBreakdown of toleranceImmune-mediated pathologyHost-directed mechanismViral componentsAntiviral CD4Lethal immunopathologyInfectious insultsImmune activationImmunological tolerance
2021
Norovirus evolution in immunodeficient mice reveals potentiated pathogenicity via a single nucleotide change in the viral capsid
Walker FC, Hassan E, Peterson ST, Rodgers R, Schriefer LA, Thompson CE, Li Y, Kalugotla G, Blum-Johnston C, Lawrence D, McCune BT, Graziano VR, Lushniak L, Lee S, Roth AN, Karst SM, Nice TJ, Miner JJ, Wilen CB, Baldridge MT. Norovirus evolution in immunodeficient mice reveals potentiated pathogenicity via a single nucleotide change in the viral capsid. PLOS Pathogens 2021, 17: e1009402. PMID: 33705489, PMCID: PMC7987144, DOI: 10.1371/journal.ppat.1009402.Peer-Reviewed Original ResearchConceptsNucleotide changesSingle nucleotide changeViral capsidAmino acid changesEvolutionary potentialIFN-competent hostsIntestinal myeloid cellsSelective pressureSingle nucleotideKey controllerNorovirus evolutionAcid changesLethal pathogenVirus growthEnhanced virulenceMice revealsIFN responseHigh replicationEnhanced recruitmentMyeloid cellsExtraintestinal disseminationIntestinal replicationReplicationPathogenicityCapsidCD300lf Conditional Knockout Mouse Reveals Strain-Specific Cellular Tropism of Murine Norovirus
Graziano VR, Alfajaro MM, Schmitz CO, Filler RB, Strine MS, Wei J, Hsieh LL, Baldridge MT, Nice TJ, Lee S, Orchard RC, Wilen CB. CD300lf Conditional Knockout Mouse Reveals Strain-Specific Cellular Tropism of Murine Norovirus. Journal Of Virology 2021, 95: 10.1128/jvi.01652-20. PMID: 33177207, PMCID: PMC7925115, DOI: 10.1128/jvi.01652-20.Peer-Reviewed Original ResearchConceptsConditional knockout miceIntestinal epithelial cellsCell tropismKnockout miceTuft cellsDendritic cellsMyelomonocytic cellsB cellsCellular tropismMurine norovirusEpithelial cellsViral RNA levelsInnate immune responseCause of gastroenteritisMNoV infectionCell typesViral loadGastrointestinal infectionsReceptor expressionImmunocompetent humansImmune responseCell type-specific rolesMouse modelIntestinal tissueMNoV
2020
CD300LF Polymorphisms of Inbred Mouse Strains Confer Resistance to Murine Norovirus Infection in a Cell Type-Dependent Manner
Furlong K, Biering SB, Choi J, Wilen CB, Orchard RC, Wobus CE, Nelson CA, Fremont DH, Baldridge MT, Randall G, Hwang S. CD300LF Polymorphisms of Inbred Mouse Strains Confer Resistance to Murine Norovirus Infection in a Cell Type-Dependent Manner. Journal Of Virology 2020, 94: 10.1128/jvi.00837-20. PMID: 32581099, PMCID: PMC7431780, DOI: 10.1128/jvi.00837-20.Peer-Reviewed Original ResearchConceptsBone marrow-derived macrophagesCell type-dependent mannerType-dependent mannerCell typesMacrophage-like cellsRobust experimental systemMNV infectionRelated murine norovirusSpecific cell typesCorresponding mutantsMarrow-derived macrophagesMurine norovirus infectionEntry factorsMurine norovirusCD300lfCause of gastroenteritisNonpermissive cellsProteinaceous receptorsConfer resistanceHuman cellsHost cellsDifferent allelesAmino acidsC57BL/6J allelePermissive cellsCD300lf is the primary physiologic receptor of murine norovirus but not human norovirus
Graziano VR, Walker FC, Kennedy EA, Wei J, Ettayebi K, Strine MS, Filler RB, Hassan E, Hsieh LL, Kim AS, Kolawole AO, Wobus CE, Lindesmith LC, Baric RS, Estes MK, Orchard RC, Baldridge MT, Wilen CB. CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus. PLOS Pathogens 2020, 16: e1008242. PMID: 32251490, PMCID: PMC7162533, DOI: 10.1371/journal.ppat.1008242.Peer-Reviewed Original ResearchConceptsMNoV infectionPrimary physiologic receptorPhysiologic receptorHuman norovirusMurine norovirusBona fide receptorHumoral responseVirus infectionEntry receptorReceptor utilizationCell tropismInfectionReceptorsVirus-like particlesFide receptorCD300lfNorovirusHNoVCD300ldMajor determinantProteinaceous receptorsVivoMNoV.MNoVPathogenesis
2019
The intestinal regionalization of acute norovirus infection is regulated by the microbiota via bile acid-mediated priming of type III interferon
Grau KR, Zhu S, Peterson ST, Helm EW, Philip D, Phillips M, Hernandez A, Turula H, Frasse P, Graziano VR, Wilen CB, Wobus CE, Baldridge MT, Karst SM. The intestinal regionalization of acute norovirus infection is regulated by the microbiota via bile acid-mediated priming of type III interferon. Nature Microbiology 2019, 5: 84-92. PMID: 31768030, PMCID: PMC6925324, DOI: 10.1038/s41564-019-0602-7.Peer-Reviewed Original ResearchConceptsNorovirus infectionType III interferonsMurine norovirus infectionCommensal bacteriaIII interferonsIntestinal microbiotaType III interferon responseBile acid receptorProximal small intestineRegional expression profilesProximal gutAntibiotic treatmentViral infectionSmall intestineIntestinal tractAcid receptorsInfectionInterferon responseMicrobiotaInterferonPathogenic enteric virusesEnteric virusesHost metabolitesGutExpression profilesBile Salts Alter the Mouse Norovirus Capsid Conformation: Possible Implications for Cell Attachment and Immune Evasion
Sherman MB, Williams AN, Smith HQ, Nelson C, Wilen CB, Fremont DH, Virgin HW, Smith TJ. Bile Salts Alter the Mouse Norovirus Capsid Conformation: Possible Implications for Cell Attachment and Immune Evasion. Journal Of Virology 2019, 93: 10.1128/jvi.00970-19. PMID: 31341042, PMCID: PMC6744230, DOI: 10.1128/jvi.00970-19.Peer-Reviewed Original ResearchConceptsCryo-EM structureP domainCryo-electron microscopy structureHigh-resolution cryo-EM structuresConformational changesImportant biological rolesSmall conformational changesMicroscopy structureHuman Norwalk virusCell attachmentAdjacent subunitsBiological roleIcosahedral capsidCapsid shellRNA virusesCapsid proteinBinding sitesIntrinsic affinityReceptor binding sitesCapsid conformationUnusual structureImmune evasionShell domainTarget cellsReceptorsNoroviruses subvert the core stress granule component G3BP1 to promote viral VPg-dependent translation
Hosmillo M, Lu J, McAllaster MR, Eaglesham JB, Wang X, Emmott E, Domingues P, Chaudhry Y, Fitzmaurice TJ, Tung MK, Panas MD, McInerney G, Locker N, Wilen CB, Goodfellow IG. Noroviruses subvert the core stress granule component G3BP1 to promote viral VPg-dependent translation. ELife 2019, 8: e46681. PMID: 31403400, PMCID: PMC6739877, DOI: 10.7554/elife.46681.Peer-Reviewed Original ResearchConceptsViral positive-sense RNAFirst host factorHost factorsPositive-sense RNAPro-viral activityPositive-sense RNA virusesSense RNA virusesG3BP1 functionsRibosome recruitmentTranslation complexesTranslation initiationCRISPR screensProteomic analysisMurine norovirus infectionReplication complexSense RNANovel functionViral translationRNA virusesG3BP1Data uncoversNorovirus replicationLife cycleVPgGenusNorovirus Attachment and Entry
Graziano VR, Wei J, Wilen CB. Norovirus Attachment and Entry. Viruses 2019, 11: 495. PMID: 31151248, PMCID: PMC6630345, DOI: 10.3390/v11060495.Peer-Reviewed Original ResearchConceptsHisto-blood group antigensNorovirus attachmentMajority of casesMajor human pathogenViral life cycleImmune interactionsViral gastroenteritisCell tropismGroup antigensViral entryKey mediatorHuman norovirusBile saltsViral genome releaseMurine norovirusReceptorsMinor capsid protein VP2Capsid protein VP2Human pathogensMolecular mechanismsNorovirusSignificant determinantsProtein VP2Important future directionsCurrent understandingA Secreted Viral Nonstructural Protein Determines Intestinal Norovirus Pathogenesis
Lee S, Liu H, Wilen CB, Sychev ZE, Desai C, Hykes BL, Orchard RC, McCune BT, Kim KW, Nice TJ, Handley SA, Baldridge MT, Amarasinghe GK, Virgin HW. A Secreted Viral Nonstructural Protein Determines Intestinal Norovirus Pathogenesis. Cell Host & Microbe 2019, 25: 845-857.e5. PMID: 31130511, PMCID: PMC6622463, DOI: 10.1016/j.chom.2019.04.005.Peer-Reviewed Original ResearchConceptsNS1 secretionTuft cellsIFN-λ responseAnti-capsid antibodiesMNoV infectionAcute infectionIntestinal infectionsLack of inductionPersistent infectionNorovirus pathogenesisCaspase-3 cleavageIFN responseInfectionSecretionViral nonstructural proteinsIFNProtein 1/2Viral proteinsMurine norovirusNS1Lower percentageNonstructural proteinsCellsLow numberVaccination
2018
Structural basis for murine norovirus engagement of bile acids and the CD300lf receptor
Nelson CA, Wilen CB, Dai YN, Orchard RC, Kim AS, Stegeman RA, Hsieh LL, Smith TJ, Virgin HW, Fremont DH. Structural basis for murine norovirus engagement of bile acids and the CD300lf receptor. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: e9201-e9210. PMID: 30194229, PMCID: PMC6166816, DOI: 10.1073/pnas.1805797115.Peer-Reviewed Original ResearchConceptsP domainCognate cellular receptorDomain dimer interfaceDimer interfaceBiophysical assaysStructural basisCD300lfResidue mutationsP2 subdomainAcid bindingCell surfaceHost ligandsCellular receptorsProtruding (P) domainStructural determinantsDE loopMonomeric affinityBinding sitesX-ray crystal structurePotential modulatorsReceptor binding sitesMNoVCrystal structureDivalent cationsReceptorsSphingolipid biosynthesis induces a conformational change in the murine norovirus receptor and facilitates viral infection
Orchard RC, Wilen CB, Virgin HW. Sphingolipid biosynthesis induces a conformational change in the murine norovirus receptor and facilitates viral infection. Nature Microbiology 2018, 3: 1109-1114. PMID: 30127493, PMCID: PMC6158067, DOI: 10.1038/s41564-018-0221-8.Peer-Reviewed Original ResearchConceptsSerine palmitoyltransferase complexSphingolipid biosynthesisCellular susceptibilityConformational changesLipid biosynthetic enzymesDe novo sphingolipid biosynthesisHost cellular receptorsSerine palmitoyltransferase activityBiosynthetic enzymesBiosynthetic pathwayMurine norovirus infectionMurine norovirusCD300lfCell surfaceBiosynthesisUnappreciated connectionCellular receptorsExtracellular ceramideReceptor conformationViral infectionSurface expressionTarget cell surfaceViral bindingPalmitoyltransferase activityReceptorsTropism for tuft cells determines immune promotion of norovirus pathogenesis
Wilen CB, Lee S, Hsieh LL, Orchard RC, Desai C, Hykes BL, McAllaster MR, Balce DR, Feehley T, Brestoff JR, Hickey CA, Yokoyama CC, Wang YT, MacDuff DA, Kreamalmayer D, Howitt MR, Neil JA, Cadwell K, Allen PM, Handley SA, van Lookeren Campagne M, Baldridge MT, Virgin HW. Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science 2018, 360: 204-208. PMID: 29650672, PMCID: PMC6039974, DOI: 10.1126/science.aar3799.Peer-Reviewed Original ResearchConceptsVirus infectionImmune promotionTuft cellsType 2 cytokinesEnteric virus infectionEnteric viral infectionsIntestinal epithelial cellsMNoV infectionNorovirus infectionCommensal microbiotaHost immunityViral infectionNorovirus pathogenesisRare typeImmune systemCellular tropismInfectionMouse intestineTarget cellsEpithelial cellsCell proliferationCytokinesTropismCD300lfCells
2017
Norovirus Cell Tropism Is Determined by Combinatorial Action of a Viral Non-structural Protein and Host Cytokine
Lee S, Wilen CB, Orvedahl A, McCune BT, Kim KW, Orchard RC, Peterson ST, Nice TJ, Baldridge MT, Virgin HW. Norovirus Cell Tropism Is Determined by Combinatorial Action of a Viral Non-structural Protein and Host Cytokine. Cell Host & Microbe 2017, 22: 449-459.e4. PMID: 28966054, PMCID: PMC5679710, DOI: 10.1016/j.chom.2017.08.021.Peer-Reviewed Original ResearchConceptsIntestinal epithelial cellsViral surface proteinsCellular tropismPersistent viral infectionNon-structural protein NS1Expression of NS1MNoV infectionSurface proteinsHost cytokinesAntiviral immunityHost determinantsInterferon lambdaViral infectionKey host determinantsViral non-structural proteinsCell tropismFecal sheddingNon-structural proteinsTropism determinantsEpithelial cellsGlobal causeInfectionTropismProtein NS1MNoV